Muscarinic cholinergic receptors (mAChRs) mediate the actions of the neurotransmitter acetylcholine in the central and peripheral nervous systems, gastrointestinal system, heart, endocrine glands, lungs, and other tissues. See Central Cholinergic Synaptic Transmission, M. Frotscher and U. Misgeld, eds., Birkhauser Verlag, Basel, 1989; Kromer, W.; Gonne, S.; Int. J. Exp. Clin. Pharmacol., 1988, 37 (suppl. 1), 48; Melchiorre, C.; Cassinelli, A.; Quaglia, W.; J. Med. Chem., 1987, 30, 201; Melchiorre, C.; Cassinelli, A.; Angeli, P.; Giardina, D.; Gulini, U.; Quaglia, W.; Trends Pharm. Sci. supplement 1988, 55; Goyal, R.; New England J. Med., 1989, 321, 1022; and Maclagan, J.; Barnes, P., Trends Pharamcol. Sci 1989 (Suppl. "Subtypes of Muscarinic Receptors IV"), ed. R. Levine and N. J. M. Birdsall, pp. 88-92, which are specifically incorporated by reference herein.
At least five distinct gene products have been identified which code A. C.; five distinct mAChRs, termed m1 through m5. See Bonner, T. I.; Buckley, N. J.; Young, A. C.; Brann, M. R.; Science 1987, 237, 527; Bonner, T. I.; Young, A. C.; Brann, M. R.; Buckley, N. J.; Neuron 1988, 1, 403; Peralta, E. G.; Ashkenazi, A.; Winslow, J. W.; Ramachandran, J.; Capon, D. J.; Nature 1988, 334, 434; and Maeda, A.; Kubo, T.; Mishina, M.; Numa, S., FEBS Lett. 1988, 239, 339, which are specifically incorporated by reference herein.
The m1, m2 and m3 receptors correlate pharmacologically to the M1, M2, and M3 (M2 glandular) receptors, respectively. See Levine, R. R.; Birdsall, N. J. M.; Subtypes of Muscarinic Receptors IV; Trends in Pharm. Sci. supplement, Vol. 10; and Elsevier Trends Journals; Cambridge UK, 1989, p. VII, which are specifically incorporated by reference herein. The ml and m3 receptors have been shown to be coupled preferentially to the stimulation of phosphoinositide metabolism, and m2 and m4 receptors have been shown to be coupled preferentially to the inhibition of adenylate cyclase. See Peralta, E. G.; Ashkenazi, A.; Winslow, J. W.; Ramachandran, J.; Capon, D. J., Nature 1988, 334, 434; and Hughes, A. R.; Martin, M. W.; Harden, T. K., Proc. Natl. Acad. Sci USA 1984, 81, 5680, which are specifically incorporated by reference herein.
Other effector systems, such as voltage-dependent and calcium-dependent potassium channels are coupled to muscarinic receptors. See Adams, P. R.; Brown, D. A.; Constanti, A., J. Physiol., 1982, 332, 223; and Yatani, A.; Hamm, H.; Codina, J.; Mazzoni, M. R., Birnbaumer, L.; Science, 1988, 241, 828, which are specifically incorporated by reference herein.
In the brain, four genetic subtypes have been localized through hybridization with oligonucleotide probes. See Bonner, T. I; Buckley, N. J.; Young, A. C.; Brann, M. R., Science 1987, 237, 527, which is specifically incorporated by reference herein. The working hypothesis that administration of a centrally active, selective muscarinic agonist would relieve the memory loss associated with Alzheimer's disease was deduced from the observed degeneration of presynaptic muscarinic terminals in the nucleus basalis region of these patients. See Fisher, A.; Brandeis, R.; Karton, I.; Pittel, Z.; Dachir, S.; Sapir, M.; Grunfeld, Y.; Levy, A.; and Heldman, E. in "Novel Approaches to the Treatment of Alzheimer's Disease" E. M. Meyer; J. W. Simpkins; J Yamamoto, eds., Advances in Behavioral Biology, Vol. 36, Plenum, New York, 1989, pp. 11-16, which is specifically incorporated herein by reference. Subsequent research prompted by this observation has led to the identification of a number of classes of muscarinic agonists. See Baker, R.; Saunders, J.; Ann. Rep. Medicinal Chem. 1989, 24, 31, which is specifically incorporated herein by reference.
In addition to the development of new agonists, there is a need to develop more highly selective muscarinic antagonists, both as pharmacological tools and as potential therapeutic agents. For example, the first known ml-selective antagonist, pirenzepine, is useful clinically in the inhibition of gastric acid production. See Hammer, R. B.; Birdsall, N. J. M.; Burgen, A. S. V.; Hulme, E. C.; Nature 1980, 283, 90; Hammer, R.; Giachetti, A.; Life Sci. 1982, 31, 2991; and Kromer, W.; Gonne, S.; Int. J. Exp. Clin. Pharmacol., 1988, 37 (suppl. 1), 48, which are specifically incorporated herein by reference.
An m3-selective antagonist would be useful in treating airway disease and atonic conditions of the gut and bladder. See Maclagan, J.; Barnes, P.; Trends Pharamcol. Sci. 1989 (Suppl. "Subtypes of Muscarinic Receptors IV"), Levine, R.; Birdsall, N. J. M.; pp. 88-92; and Mutschler E.; Feifel, R.; Moser, U.; Tacke, R.; Wess, J.; Lambrecht, G.; Eur. J. Pharmacol. 1990, 183, 117, which are specifically incorporated by reference herein. An m4-selective antagonist would be useful in the control of hyperreactivity of smooth muscle. See Mutschler E.; Feifel, R.; Moser, U.; Tacke, R.; Wess, J.; Lambrecht, G.; Eur. J. Pharmacol. 1990, 183, 117, which is specifically incorporated by reference herein.
Previous studies by the inventors of structure activity relationships in analogues of the muscarinic agonist oxotremorine utilized a functionalized congener approach, i.e. chemically functionalized chains were incorporated at sites on the pharmacophore that were insensitive to this modification in receptor binding. See Bradbury, B. J.; Baumgold, J.; Jacobson, K. A.; J. Med. Chem., 1990, 33:741-748; and Bradbury, B. J.; Baumgold, J.; Paek, R.; Kammula, U.; Zimmet, J.; Jacobson, K. A.; J. Med. Chem., 1991, 34:1073-1079, which are specifically incorporated by reference herein.
Functionalized congeners in other drug classes have been useful in affinity chromatography to purify receptors, in the synthesis of selective affinity labels, and in prodrug design. See Jacobson, K. A.; Daly, J. D.; Nucleosides and Nucleotides, 1991, 10: 1029-1038; and Barone, S.; Churchill, P. C.; Jacobson, K. A.; J. Pharm. Exp. Therap. 1989, 250, 79, which are specifically incorporated by reference herein.
The inventors have now extended the functionalized congener approach to analogues of the selective muscarinic antagonists pirenzepine 1 and telenzepine 3.